Differential anti-inflammatory effects of LPS in susceptible and resistant mouse strains

Most mouse strains are highly susceptible to endotoxin (LPS) lethality and are responsive to LPS stimulation in vitro (e.g., B cell mitogenesis, macrophage activation). They are, however, capable of mounting only a small inflammatory response to LPS when it is injected i.p. The present study demonstrates that LPS is in fact a potent, anti-inflammatory agent in all of the five normally LPS susceptible strains tested. LPS was also anti-inflammatory in F1 hybrid mice from susceptible (C3HeB/FeJ) x-resistant (C3H/HeJ) parents. Anti-inflammatory effects of LPS in susceptible strains were achieved by either i.v. or i.p. treatment and were observed toward a variety of phlogistic stimuli including mitogens, C-activating substances, and nonspecific irritants. The most dramatic inhibitory effect of LPS was directed toward the accumulation of inflammatory macrophages. Kinetic studies indicated that the anti-inflammatory effect of a single dose of LPS persisted for at least 72 hr but was maximal when LPS was given simultaneously with the inflammatory stimulus. In contrast to normal mice, two mutant, LPS resistant strains (C3H/HeJ and C57BL10/ScCR) responded to increasing doses of LPS i.p. with a progressively increasing influx of inflammatory cells. In addition, in resistant strains, LPS often enhanced and never depressed the inflammatory response to other phlogistic agents. These studies demonstrate that the genetic regulation of the inflammatory responses to LPS also controls the anti-inflammatory effects of LPS. These responses may be another relevant parameter in determining strain susceptibility to LPS lethality.